ANALYSIS AND INTERPRETATION OF LIGAND-DNA BINDING ISOTHERMS

By Q. LUANA

I INTRODUCTION THE BASIC PRINCIPLES OF GRID INTRODUCTION PHILOSOPHY AND OBJECTIVES PRIORITIES THE GRID METHOD GRID PROBES ARE ANISOMETRIC THE TARGET “RESPONDS” TO THE PROBE THE TARGET IS IMMERSED IN WATER THE GRID FORCE FIELD THE LENNARD-JONES TERM THE ELECTROSTATIC TERM THE HYDROGEN BOND TERM THE OTHER TERMS NOMENCLATURE “ATOM” RECORDS “HETATM” RECORDS CALIBRATING THE GRID FORCE FIELD CHECKING THE CALIBRATION CHECKING DATAFILE GRUB THE OUTPUT FROM GRID GRID MAPS FROM MACROMOLECULES GRID MAPS FROM A SMALL MOLECULE CONCLUSIONS CONTENTS CALCULATION AND APPLICATION OF MOLECULAR INTERACTION FIELDS CALCULATION OF MIFS THE TARGET THE PROBE THE INTERACTION FUNCTION VAN DER WAALS INTERACTIONS ELECTROSTATIC INTERACTIONS HYDROGEN BONDS ENTROPY SELECTED APPLICATIONS OF MIFS MAPPING A LIGAND BINDING SITE IN A PROTEIN DERIVING 3D-QSARS SIMILARITY ANALYSIS OF A SET OF RELATED MOLECULES CONCLUDING REMARKS AND OUTLOOK II PHARMACODYNAMICS PROTEIN SELECTIVITY STUDIES USING GRID-MIFS GRID CALCULATIONS AND CHEMOMETRIC ANALYSIS SOURCE AND SELECTION OF TARGET STRUCTURES SELECTION AND SUPERIMPOSITION OF BINDING SITES CALCULATION OF THE MOLECULAR INTERACTION FIELD MATRIX GENERATION AND PRETREATMENTS REGION CUT-OUTS GRID/PCA SCORE PLOTS TWO-DIMENSIONAL LOADING PLOTS LOADING CONTOUR MAPS PROBLEMS OF GRID/PCA GRID/CPCA BLOCK UNSCALED WEIGHTS CPCA IDENTIFICATION OF IMPORTANT VARIABLE BLOCKS FOR SELECTIVITY CONTOUR PLOTS APPLICATIONS DNA MINOR GROOVE BINDING – COMPARE AAA AND GGG DOUBLE HELIX DIHYDROFOLATE REDUCTASE CYCLOOXYGENASE PENICILLIN ACYLASE SERINE PROTEASES S1 POCKET P POCKET D POCKET TARGET FAMILY LANDSCAPES OF PROTEIN KINASES MATRIX METALLOPROTEINASES (MMPS) NITRIC OXIDE SYNTHASES PPARS BILE ACID TRANSPORTATION SYSTEM EPHRIN LIGANDS AND EPH KINASES DISCUSSION AND CONCLUSION FLAP: 4-POINT PHARMACOPHORE FINGERPRINTS FROM GRID PHARMACOPHORES AND PHARMACOPHORE FINGERPRINTS FLAP FLAP THEORY DOCKING GLUE: A NEW DOCKING PROGRAM BASED ON PHARMACOPHORES CASE STUDY STRUCTURE BASED VIRTUAL SCREENING (SBVS) LIGAND BASED VIRTUAL SCREENING (LBVS) PROTEIN SIMILARITY TOPP (TRIPLETS OF PHARMACOPHORIC POINTS) THE COMPLEXITY OF MOLECULAR INTERACTION: MOLECULAR SHAPE FINGERPRINTS BY THE PATHFINDER APPROACH BACKGROUND THE PATHFINDER APPROACH PATHS FROM POSITIVE MIF PATHS FROM NEGATIVE MIF EXAMPLES 3D-QSAR CYP COMPARISON TARGET–LIGAND COMPLEXES ALIGNMENT-INDEPENDENT DESCRIPTORS FROM MOLECULAR INTERACTION FIELDS THE NEED FOR MIF-DERIVED ALIGNMENT-INDEPENDENT DESCRIPTORS GRIND APPLICATIONS GRIND THE BASIC IDEA COMPUTATION OF MIF EXTRACTION OF HIGHLY RELEVANT REGIONS MACC2 ENCODING THE ANALYSIS OF GRIND VARIABLES HOW TO INTERPRET A GRIND-BASED 3D QSAR MODEL OVERVIEW INTERPRETING CORRELOGRAMS INTERPRETING SINGLE VARIABLES GRIND-BASED 3D QSAR MODELS ARE NOT PHARMACOPHORES GRIND LIMITATIONS AND PROBLEMS GRIND AND THE LIGAND CONFORMATIONS THE AMBIGUITIES CHIRALITY RECENT AND FUTURE DEVELOPMENTS LATEST DEVELOPMENTS SHAPE DESCRIPTION ANCHOR GRIND THE FUTURE 3D-QSAR USING THE GRID/GOLPE APPROACH GRID/GOLPE APPLICATION EXAMPLES ESTROGEN RECEPTOR LIGANDS ACETYLCHOLINESTERASE INHIBITORS CONCLUSION III PHARMACOKINETICS USE OF MIF-BASED VOLSURF DESCRIPTORS IN PHYSICOCHEMICAL AND PHARMACOKINETIC STUDIES ADME PROPERTIES AND THEIR PREDICTION VOLSURF DESCRIPTORS APPLICATION EXAMPLES AQUEOUS SOLUBILITY OCTANOL/WATER PARTITION COEFFICIENTS VOLUME OF DISTRIBUTION (VD) METABOLIC STABILITY MOLECULAR INTERACTION FIELDS IN ADME AND SAFETY GRID AND MIFS ROLE OF PGP EFFLUX IN THE ABSORPTION MATERIALS AND METHODS DATASET COMPUTATIONAL METHODS ALMOND DESCRIPTORS RESULTS PHARMACOPHORIC MODEL INTERPRETATION DISCUSSION HERG INHIBITION NONBASIC NITROGEN SUBSET IONIZABLE NITROGEN SUBSET INTERPRETATION OF PHARMACOPHORIC MODELS CYP 3A4 INHIBITION LIGAND GRIND DESCRIPTORS PROTEIN GRIND DESCRIPTORS OVERLAP OF STRUCTURES DISTANCES IN THE PROTEIN POCKET PROGRESS IN ADME PREDICTION USING GRID-MOLECULAR INTERACTION FIELDS INTRODUCTION: ADME FIELD IN THE DRUG DISCOVERY PROCESS ABSORPTION PASSIVE TRANSPORT, TRANS-CELLULAR PATHWAY ACTIVE TRANSPORT DISTRIBUTION SOLUBILITY UNSPECIFIC PROTEIN BINDING VOLUME OF DISTRIBUTION METABOLISM CYTOCHROME P450 INHIBITION SITE OF METABOLISM PREDICTION SELECTIVITY ANALYSIS RAPID ADME FILTERS FOR LEAD DISCOVERY THE RULE OF FIVE (RO5) AS ADME FILTER MOLECULAR INTERACTION FIELDS (MIFS): VOLSURF MIF-BASED ADME MODELS CLINICAL PHARMACOKINETICS (PK) AND TOXICOLOGICAL (TOX) DATASETS VOLSURF IN CLINICAL PK DATA MODELING CHEMGPS-VOLSURF (GPSVS) IN CLINICAL PK PROPERTY MODELING PENGUINS: ULTRAFAST ADME FILTER INTEGRATED ADME AND BINDING AFFINITY PREDICTIONS GRID-DERIVED MOLECULAR INTERACTION FIELDS FOR PREDICTING THE SITE OF METABOLISM IN HUMAN CYTOCHROMES CYPS CHARACTERIZATION USING GRID MOLECULAR INTERACTION FIELDS DESCRIPTION OF THE METHOD P450 MOLECULAR INTERACTION FIELDS TRANSFORMATION 3D STRUCTURE OF SUBSTRATES AND FINGERPRINT GENERATION SUBSTRATE–CYP ENZYME COMPARISON: THE RECOGNITION COMPONENT THE REACTIVITY COMPONENT COMPUTATION OF THE PROBABILITY OF A SITE BEING THE METABOLIC SITE AN OVERVIEW OF THE MOST SIGNIFICANT RESULTS IMPORTING DIFFERENT P450 CYTOCHROMES SOFTWARE PACKAGE